Keytruda

Pembrolizumab (Keytruda) Instructions

Common name: Pembrolizumab
Trade name: Keytruda
All names: Pembrolizumab, Keytruda, K-drug, Keytru da, Pembrolizumab

Indications:
Pembrolizumab combined with chemotherapy (carboplatin combined with paclitaxel) is a first-line treatment for metastatic squamous non-small cell lung cancer (lung squamous cell carcinoma), regardless of PD-L1 expression status. It can also be used for the treatment of unresectable or metastatic melanoma that has failed first-line treatment.

Usage and Dosage:
The recommended dosage regimen of pembrolizumab in melanoma is 2 mg/kg intravenous infusion over 30 minutes, administered every 3 weeks until disease progression or unacceptable toxicity occurs. For non-small cell carcinoma, 200 mg is administered intravenously every three weeks until disease progression or unacceptable toxicity.

Adverse reactions:
≥10%
Fatigue (21%)
Pruritus (16%)
Skin rash (13%)
Diarrhea (12%)
Nausea (10%)
Hypothyroidism (23.3%)
Hypertriglyceridemia (20.4%)
Elevated blood lactate dehydrogenase ( 15.5%)
Elevated alanine aminotransferase (14.6%)
Decreased white blood cell count (11.7%)
Anemia (10.7%)
Hyperglycemia (10.7%)
Elevated blood bilirubin (10.7%)

<10%
Elevated aspartate aminotransferase ( 9.7%)
Decreased neutrophil count (9.7%)
Hyperuricemia (8.7%)
Decreased appetite (7.8%)
Elevated conjugated bilirubin (6.8%)
Elevated blood creatine kinase (6.8%)
Hyperthyroidism (5.8%)
Fatigue (5.8%)
Elevated blood cholesterol ( 5.8%)

Contraindications:
Contraindicated for those allergic to the active ingredients and excipients of brolizumab.

Precautions:
Immune-related Nephritis
Nephritis has been reported in patients receiving pembrolizumab. Patients should be monitored for changes in renal function and other causes of renal impairment should be excluded. Administer corticosteroids for grade ≥ 2 nephritis (initial dose 1-2 mg/kg/day prednisone or equivalent, followed by tapering). Depending on the severity of the creatinine rise, pembrolizumab should be withheld in patients with grade 2 nephritis and withholding in patients with grade 3 or 4 nephritis.

Immune-related endocrine diseases
Severe endocrine diseases, including hypophysitis, type 1 diabetes, diabetic ketoacidosis, hypothyroidism, and hyperthyroidism, may occur with pembrolizumab treatment.
When immune-related endocrine diseases occur, long-term hormone replacement therapy may be required.
Rejection of solid organ transplants has been reported in patients receiving PD-1 inhibitors post-marketing. Treatment with pembrolizumab may increase the risk of solid organ transplant rejection. The benefits of pembrolizumab treatment should be weighed against the possible risk of organ rejection in these patients.

Complications of allogeneic hematopoietic stem cell transplantation (HSCT)
Treatment with pembrolizumab after allogeneic HSCT
In patients who have previously received allogeneic HSCT, acute graft-versus-host disease (GVHD), including fatal GVHD, has been reported after treatment with pembrolizumab. Patients who develop GVHD after transplant surgery may be at increased risk for GVHD after treatment with pembrolizumab. For patients who have undergone allogeneic HSCT, the benefits of pembrolizumab treatment should be considered against the possible risk of GVHD.

Patients excluded from clinical trials
Patients with the following conditions were excluded from clinical trials: active central nervous system metastases; ECOGPS ≥2; HIV, hepatitis B, or hepatitis C infection; active systemic autoimmune disease; interstitial lung disease; previous pneumonia requiring systemic corticosteroid therapy; response to another single disease Clonal antibodies have a history of severe allergies; are receiving immunosuppressive therapy and have a history of severe immune-related adverse reactions (defined as any grade 4 toxicity or grade 3 toxicity requiring more than 12 weeks of corticosteroid therapy (>10 mg/day prednisone or equivalent) with pilimumab). Patients with active infections requiring systemic treatment were excluded from clinical trials. Patients with clinically significant abnormalities in the kidneys (creatinine >1.5xULN) or liver (bilirubin >1.5xULN, ALT, AST >2.5xULN, no liver metastases) at baseline were also excluded from the clinical trial; therefore, information is limited in patients with severe renal impairment and moderate-to-severe hepatic impairment.

Infusion-Related Reactions
Severe infusion-related reactions, including hypersensitivity and anaphylaxis, have been reported in patients receiving pembrolizumab. For severe infusion reactions, the infusion must be stopped and pembrolizumab discontinued. Patients who experience mild or moderate infusion reactions can continue to receive pembrolizumab treatment under close monitoring; antipyretic, analgesic, anti-inflammatory drugs and antihistamines can be considered for prevention.

Multiple Myeloma
For patients with multiple myeloma, the mortality rate increased after the addition of pembrolizumab to thalidomide analogues and dexamethasone.
In two randomized clinical trials in patients with multiple myeloma, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone (PD-1 or PD-L1 blocking antibodies are not approved for this indication) resulted in increased mortality. Except in controlled clinical trials, the use of PD-1 or PD-L1 blocking antibodies in combination with thalidomide analogues and dexamethasone is not recommended for the treatment of patients with multiple myeloma.

Embryotoxicity
Based on its mechanism of action, use of Keytruda during pregnancy may cause harm to the fetus. Animal models have linked the PD-1/PD-L1 signaling pathway to maintenance of pregnancy by inducing maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, the patient should be informed of the potential harm to the fetus. It is recommended that women of childbearing potential use contraceptive methods during pembrolizumab treatment and continue to do so for 4 months after a dose of pembrolizumab.

Incompatibilities
Keytruda shall not be mixed with other pharmaceutical products without conducting compatibility studies. Keytruda should not be co-infused with other medicinal products through the same intravenous channel.
Effects on ability to drive and operate machinery.
Pembrolizumab may have a mild effect on the ability to drive and operate machinery. Fatigue has been reported following administration of pembrolizumab.

Storage:
Save the vials in the original packaging in a refrigerated environment of 2°C to 8°C, away from light, freezing, and shaking.

Mechanism of action:
The PD-1 receptor expressed by T cells binds to its ligands PD-L1 and PD-L2, which can inhibit T cell proliferation and cytokine production. The PD-1 ligand of some tumor cells is up-regulated, and signaling through this pathway can inhibit the immune surveillance of tumors by activated T cells. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor. It blocks the interaction between PD-1 and PDL1 and PD-L2, and relieves the suppression of immune responses mediated by the PD-1 pathway, including anti-tumor immune responses. In a syngeneic mouse model of swelling and pain, blocking PD-1 activity inhibited tumor growth.

Efficacy and safety:
Whether it is global data or Chinese data alone, K drug is better than the chemotherapy group in terms of survival and side effects.
Global data: Among global PD-L1-positive (TPS ≥ 1%) lung cancer patients, the median overall survival of pembrolizumab and chemotherapy was 16.7 months and 12.1 months, respectively.
Chinese data: Among Chinese PD-L1-positive (TPS ≥ 1%) lung cancer patients, the median overall survival (OS) of pembrolizumab and chemotherapy were 20.0 months and 13.7 months respectively, improving survival by nearly half a year.
In addition to prolonging the patient's survival, K drug has an absolute advantage in side effects. The incidence of grade 3 and above side effects is 17%, compared with 68% for chemotherapy!
KEYNOTE-426 is a randomized, multi-center, open-label study conducted in 861 patients with advanced RCC (regardless of tumor PD-L1 expression status) who have not received systemic therapy before, comparing the Keytruda + Inlyta regimen with the first-line standard care drug Sutent for advanced RCC.
This study shows that in patients with advanced RCC, compared with Sutent (generic name: sunitinib), the first-line standard care drug for advanced RCC, the Keytruda + Inlyta regimen reduces the risk of death by 47% (HR=0.53 [95% CI: 0.38, 0.74], p=0.00005), while improving progression-free survival (PFS) and objective response rate (ORR).

In the study, patients were randomly entered into 2 treatment groups:
(1) Keytruda+Inlyta treatment group, received intravenous infusion of 200 mg Keytruda every 3 weeks, and oral administration of 5 mg Inlyta twice daily;
(2) Sutent treatment group, received 50 mg Sutent once daily, for 4 weeks and 2 weeks off. All patients continued treatment until disease progression or unacceptable toxicity was confirmed. Keytruda can be treated for up to 24 months.

The detailed data announced at the ASCO-GU meeting are as follows: The study achieved the primary endpoints of OS, PFS and key secondary endpoints of ORR:
(1) Compared with the Sutent treatment group, the Keytruda + Inlyta treatment group had a statistically significant improvement in OS and a 47% reduction in the risk of death (HR=0.53 [95% CI: 0.38, 0.74], p=0.0005); 59 events (14%) were observed in the Keytruda+Inlyta treatment group (n=432), and 97 events (23%) were observed in the Sutent treatment group (n=429). The median OS of the two treatment regimens was not reached.
(2) Compared with the Sutent treatment group, the Keytruda+Inlyta treatment group also showed an improvement in PFS and a 31% reduction in the risk of disease progression or death (HR=0.69 [95% CI: 0.57, 0.84], p=0.00012); 183 events (42%) were observed in the Keytruda+Inlyta treatment group and 213 events (50%) were observed in the Sutent treatment group; the median PFS in the Keytruda+Inlyta treatment group was 15.1 months. (95% CI: 12.6, 17.7), the median PFS in the Sutent treatment group was 11.0 months (95% CI: 8.7, 12.5).
(3) The ORR of the Keytruda+Inlyta treatment group was 59% (95%CI: 54,64), and the ORR of the Sutent treatment group was 36% (95%CI: 31,40) (p<0.0001); the Keytruda+Inlyta treatment group had a complete response rate of 6% and a partial response rate of 53%, while the Sutent treatment group had a complete response rate of 2% and a partial response rate of 34%.
(4) The median DOR of the Keytruda+Inlyta treatment group was not reached (range: 1.4+ to 18.2+ months), and the median DOR of the Sutent treatment group was 15.2 months (range: 1.1+ to 15.4+ months).
(5) The therapeutic benefit of Keytruda + Inlyta was observed in all subgroups of patients, including all IMDC risk and PD-L1 expression subgroups.
(6) The incidence of grade 3-5 treatment-related adverse events was 76% in the Keytruda+Inlyta treatment group and 71% in the Sutent treatment group.